22-17108749-C-T

Position:

• chr22-17108749-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014339.7(IL17RA):​c.1530C>T​(p.Asp510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,611,452 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: IL17RA NM_014339.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0380

Genes affected

IL17RA (HGNC:5985): (interleukin 17 receptor A) Interleukin 17A (IL17A) is a proinflammatory cytokine secreted by activated T-lymphocytes. It is a potent inducer of the maturation of CD34-positive hematopoietic precursors into neutrophils. The transmembrane protein encoded by this gene (interleukin 17A receptor; IL17RA) is a ubiquitous type I membrane glycoprotein that binds with low affinity to interleukin 17A. Interleukin 17A and its receptor play a pathogenic role in many inflammatory and autoimmune diseases such as rheumatoid arthritis. Like other cytokine receptors, this receptor likely has a multimeric structure. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-17108749-C-T is Benign according to our data. Variant chr22-17108749-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340600.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr22-17108749-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.038 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (322/152364) while in subpopulation NFE AF= 0.00335 (228/68036). AF 95% confidence interval is 0.00299. There are 1 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.1530C>T	p.Asp510=	synonymous_variant	13/13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.1428C>T	p.Asp476=	synonymous_variant	12/12		NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.1530C>T	p.Asp510=	synonymous_variant	13/13	1	NM_014339.7	ENSP00000320936	P2
IL17RA	ENST00000612619.2	c.1428C>T	p.Asp476=	synonymous_variant	12/12	5		ENSP00000479970	A2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152246 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00211 AC: 515 AN: 244370 Hom.: 0 AF XY: 0.00195 AC XY: 259 AN XY: 132984

Gnomad AFR exome AF: 0.000385

Gnomad AMR exome AF: 0.000381

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00562

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00250 AC: 3648 AN: 1459088 Hom.: 4 Cov.: 64 AF XY: 0.00260 AC XY: 1888 AN XY: 725830

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152364 Hom.: 1 Cov.: 34 AF XY: 0.00203 AC XY: 151 AN XY: 74504

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00324 Hom.: 1

Bravo AF: 0.00173

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	IL17RA: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial Candidiasis, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Immunodeficiency 51 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148319877; hg19: chr22-17589639;